This
dramatic title refers to the cost of treatment of schistosomiasis with
praziquantal.

Schistosomiasis
is an infection caused by parasitic worms, or helminths., of the genusSchistosoma.Most of the 200 million cases of
schistosomiasis in the world occur in Africa.

The species,
Schistosoma haematobium is estimated to infect about 112 million people in sub
Saharan Africa.So its high prevalence puts
it in the same class as that of TB, malaria and HIV infection.It is responsible for a huge burden of
morbidity particularly in children and young adults.S. haematobium infection predominantly
involves the urinary tract. S. mansoni is
another species; it affects the intestinal tract.

S. haematobium
has a complicated life cycle, some of which takes place in snails. People are infected by organisms released by
snails living in fresh water. These organisms can penetrate the skin of any
body part that is immersed in snail infested water.The disease it causes is commonly called bilharzia.

I was very
conscious of its danger growing up in Zimbabwe, where prominent signs at several
small lakes around Bulawayo warned one not to swim in them because of the
danger of bilharzia.

There already is a substantial literature that strongly
suggests that many endemic infections, not only caused by helminths, but also by bacteria, protozoa, viruses
and even common intestinal worms can accelerate the progression of HIV disease and facilitate transmission of the virus . Some of the
mechanisms underlying these HIV enhancing effects have been understood for many
years.In Europe and N. America the
ability of an intercurrent infection to accelerate HIV replication is known
from the understanding that viral load testing may show a temporary increase if
done during a febrile illness, or even following a vaccination.

The paper
cited above, whose lead author is Peter Hotez, concentrates on the local effects of S. haematobium on the female
genital tract, where lesions caused by schistosome egg deposition result in
mucosal patches, that can bleed during sexual intercourse. The authors state
"Presumably, the schistosome egg granulomas produce genital lesions and mucosal
barrier breakdown to facilitate HIV viral entry" and go on to compare this to
the process by which herpes simplex ulcers increase susceptibility to HIV.

This does
seem obvious - there is a mucosal break, so HIV not only has a way in, but will find an accumulation of susceptible CD4 cells at the site of entry. But in this case what appears to be so obvious
may not be the important connection between schistosomiasis and susceptibility to HIV infection.

In fact in
the case of herpes simplex, this seemingly obvious connection between a genital
ulcer and a mode of entry for HIV is probably not correct.The large
Partners in Prevention study, recently completed, found that acyclovir, a drug
effective in treating herpes does not reduce the risk of HIV transmission.The drug however was associated, as expected,
with a reduction in the number of recurrences of herpetic ulcerations, but also
appeared to significantly slow the course of HIV disease progression. Since the probability of transmitting HIV is related to viral load then it is quite possible that while acyclovir may not prevent acquisition of HIV it may reduce the infectivity of people harbouring both HIV and a herpes virus.

There are in fact many interconnections
between HIV disease and herpesvirus infections, but I will leave a description
of these for another post.

As with
herpes simplex, it is possible that systemic effects of schistosomiasis, may be
much more significant than local effects in enhancing susceptibility to HIV infection.More recently, in direct experiments, acute infection with S. mansoni was shown to increase susceptibility to mucosal infection of Rhesus macaques by SHIV (a monkey adapted virus). Of
course, both local and systemic effects may play a role in enhancing HIV
transmission.

There are multiple systemic effects associated with many different infections that can accelerate HIV disease progression. Schistosomiasis and some other endemic infections are associated with an impairment of virus specific immune responses. Immune responses may be blunted by several mechanisms. Immune activation will probably also increase susceptibility to HIV and promote its replication. Schistosomiasis and other endemic infectious diseases are also associated with an
increased densityon the cell surface of
the chemokine co-receptors used by HIV which would increase infectability. Pro-inlammatory cytokines such as TNF-alpha and IL 6 that appear during the course of many infectious diseases are potent promoters of HIV replication.

Thus highly prevalent endemic infections can enhance HIV replication by multiple mechanisms. It is likely that this association will also be expressed clinically and has implications for the effective control of HIV in populations where these infections are common.

There have been studies showing that treatment of some of the common endemic infections can lower HIV levels, although it must also be said that not all of the studies agree on this.

Controlling these infections includes inexpensive traditional public health interventions such as supplying clean water and sanitation.

Here is the abstract of an article published
in 2006 by W.E.Secor of the CDC, dealing with schistosomiasis, but also applicable to many other infections :

"Interactions between schistosomiasis and infection
with HIV-1

In many regions of the world,
both schistosomiasis and HIV/AIDS are endemic, resulting in patients harbouring
co-infections. Because interaction with host CD4+T cells is a characteristic of schistosome as well as HIV-1 infections,
bi-directional disease effects may be sufficiently different from sequelae
caused by either infectious agent alone to warrant alteration of public health
approaches in areas of co-endemnicity. Studies published over the past decade
provide useful insights into interactions between schistosomiasis and infection
with HIV-1, and overall support the hypothesis that special emphasis on
treatment of schistosomiasis in populations with elevated prevalence or risk of
HIV-1 infection is justified".

Schistosomiasis is but one of many infections where there is a bi-directional interaction with HIV, and where the above comments have equal relevance.

Peter Hotez does a great service by
continuing tobring attention to a
number of devastating neglected tropical diseases. Many have been shown to interact with HIV, but not all by the same mechanisms.

This important article can be seen in the
Lancet of May 2nd, 2009, (Lancet 2009 373;1570-1575). I have copied the following table from this article.

The title of
the article is:

"Rescuing the bottom billion through control of neglected tropical
diseases"

By Peter J Hotez, Alan fenwick, Lorenzo savioli and David Molyneux

Many of
these infections occur in children and young adults and not only can have an
impact on life expectancy, but significantly, are the cause of chronic debility
particularly in young people.And again, as noted many of these infections also
have an activating effect on HIV replication by some mechanisms that have been
understood for well over ten years.

Despite a
great deal of evidence for the interaction of multiple bacterial, viral,
protozoal and helminthic infections with HIV, this association seems to have been
relatively neglected as a target in the fight against HIV.Of
course we do not need to justify efforts to improve the health of populations by attempting to prevent and treat highly prevalent endemic infectious diseases, but because of disease interactions, funds available to
fight HIV could very appropriately be used to combat other infections as well.We can cure and prevent many of these endemic infections,
quite often by means that are relatively inexpensive.

To summarize, the health
of hundreds of millions of individuals could be improved by efforts to prevent
and treat these infections. These
infections are also appropriate therapeutic targets in the fight against
HIV/AIDS.

HIV disease is not unique in its susceptibility to modification in a host infected with other pathogens. HIV itself can modify the course of other infectious diseases. It may however be unique in that we probably know much more about the mechanisms by which the course of HIV disease can be modified in a host also infected with other disease causing agents. We know much more about interactions between pathogenic micro-organisms through the study of HIV. So this is yet another example of the way HIV research has advanced our general understanding of the pathogenesis of infectious diseases.

Interestingly there are a few examples where the interaction of other infections may temporarily ameliorate HIV disease.Scrub typhus, measles and a form of viral hepatitis, may have a very temporary beneficial effect on
HIV disease, but these are exceptional cases. Most co-infections have the
opposite effect.

Why have
endemic diseases been so neglected in our attempts to control AIDS,
particularly in parts of Africa? We have known about some of the interactions for over twenty years; there is no shortage of publications where they have been described. Is it possible that one answer may lie in the lack of effective communication between the different disciplines engaged in HIV research? How do public health experts become informed of advances in microbiology particularly when the field of microbiology itself is changing as a result of new knowledge concerning basic mechanisms? A related issue
concerns how funders and policy makers receive the technical information they need
to make their decisions.

Also, in so far as public opinion can influence policy, information about the effects of common infections on HIV disease has not been widely reported on.

About two years ago I used a particular article to invite some discussion about these questions.

The title of this article is "Contribution
of Immune Activation to the Pathogenesis and transmission of HIV type 1
infection"; the authors are Stephen
Lawn, Salvatore Butera and Thomas Folks.
(Clinical Microbiology Reviews. Oct 2001 14; 753-777)

This is an account of observations made by microbiologists
and work done at a molecular level with enormous implications for the control
of AIDS particularly in parts of Africa where co-infections are frequent. The review
explains in great technical detail how the replication of HIV can be enormously
enhanced by concurrent endemic infections, and how this not only accelerates
the progression of HIV disease, but also facilitates its transmission. The
authors show in molecular detail how many viral, bacterial, protozoan and
helminthic infections can affect HIV replication. Included among these are common intestinal worms
and water borne bacterial infections, causing severe diarrhea particularly in
infants.

Because of the immunological and molecular
detail, I wondered if this review might present some difficulties to those not familiar with the technical terminology and thus the public health implications might not be so evident.. This particular paper is a great illustration of the
compartmentalization of information, and the difficulties of interdisciplinary
communication.

Here is an illustration from the body of the article: there
is much more just like this. A person
with no experience of molecular biology or virology would not be likely to spend much time with it.

However if one turned a few pages the following diagram might be of some interest.

The part that would
be of interest to a public health professional is contained in the large arrow at the bottom
right of the illustration. In this
rather complex and busy diagram it would be quite easy to be sufficiently distracted so that the bottom right hand corner would
be easily missed.

There is a long discussion which is quite technical in nature but at
least the authors find space for the following brief comment.

Prevention and
Treatment of Coinfections

The widespread use of HAART in
the treatment of HIV-

infected persons in
westernized countries has resulted in a

phenomenal decrease in
the incidence of opportunistic infec-

tions and has greatly
increased survival. For these individuals,

the antiretroviral
drugs are the major determinant of prognosis

and the potential
cofactor effect of opportunistic infections is

now a more minor
consideration. However, the vast majority

(>95%) of the
world's HIV-infected people do not currently

have access to
antiretroviral drugs. Most of these people live in

developing countries,
where the quality and access to health

care is often limited
and where there is a high incidence of

endemic infectious
diseases such as malaria, TB, and infections

by helminths and
waterborne pathogens which may adversely

affect HIV-1 disease
progression. Prevention or early treat-

ment of these diseases
may therefore represent an important

strategy in addressing
the HIV-1 epidemic in developing coun-

tries.

There is quite a long section on possible ways to reduce the immune activation associated with endemic infections, but the last sentence isthe only reference that deals with treating and preventing these co-infections.

Clinical Microbiology Reviews where the article appeared is a journal published by the American Society for Microbiology and presumably read mostly by microbiologists. How does the information it contains, as well as an assessment of its relevance find its way to those who advise funders and policy makers and those who inform the public?

In the above quotation, the authors are overoptimistic in
their assertion that the HIV enhancing effect of opportunistic infections is
now a more minor consideration in Europe
and N. America. Valacyclovir, a drug
that inhibits the replication of many members of the herpes virus group, but
has no direct effect on HIV (unless it is phosphorylated in a cell infected with both viruses, which is unlikely to be of practical significance) was reported to reduce HIV viral loads in the
absence of antiretroviral therapy. In
the developed world, active herpes virus infections are common in the setting
of HIV infection, although most will be asymptomatic. For example, cytomegalovirus, Epstein Barr Virus are not
infrequently found to be active in HIV infected individuals. Valacyclovir will have an effect on these
viruses, and may well find a place in the treatment of HIV infection in
developed countries. Fortunately this
drug is already prescribed quite frequently, but often only to those with evidence
of herpesvirus type 2 infections, in
order to reduce herpesvirus shedding.

Thus endemic
infections in Africa have everything to do with HIV/AIDS.There are numerous preventative and
therapeutic measures available to control many of these infections.Even something as simple as deworming may be
useful.Ascaris lumbricoides, the common
intestinal round worm also is associated with immune activation and is easily
got rid of.There is a report that doing
this with a drug called albendazole actually raised CD4 counts. (Walson
JL et al. Albendazole treatment of HIV-1 and helminth co-infection: a
randomized, double-blind, placebo-controlled trial. AIDS 22:1601-1609,
2008).

The person who has been studying immune activation and the
association of parasitic infestations and AIDS for the longest time is Zvi Bentwich.
I can't remember when his
first publication on this issue appeared
but by the mid 1990s he was publishing on this association in Ethiopian immigrants
to Israel. Zvi Bentwich deserves the
greatest credit for his early recognition of the importance of this
association, and his continuing contributions.
He pointed out the relevance of schistosomiasis to AIDS (and TB) at least 10 years ago. (We share a very long standing interest in the role of alpha interferon in the pathogenesis of HIV disease,
also something that I will leave for another post).

The connection of so many endemic infections with AIDS in Africa is also a connection of poverty
with AIDS. Of
course poverty does not cause AIDS, nor ascariasis, schistosomiasis,
tuberculosis, nor any infection. But the acquisition of many endemic infections is facilitated in impoverished populations resulting in lives that are ravaged and shortened.

Many of these infections also interact with HIV to compound the
devastation they cause. Poverty,
multiple endemic infections and HIV are intimately intertwined and in many
instances reciprocally affect and reinforce each other.

If our goal is to improve the health of populations, where multiple infections commonly co-exist, we cannot adequately manage any one of them without also considering the other infections that may be present, both in the individual and in the community.

A simple analogy would be that it is easier to kick someone when they are already down. It doesn't matter how they got ton the ground to start with. For 25 years we have heard about methods of disease transmission, but discussion of diseases that facilitate transmission has always dwelled on a very narrow focus. Now that so many small aspects of HIV infection are understood, it is time to start looking at large groups of these aspects as a whole, since HIV is such a complex, involved, changing and interacting virus. Broad pictures can be confusing if you dwell on the minute of each ingredient, but sometimes there is the wow of recognition in what was not seen before.